Profile

Research Description

I am interested in disease caused by genetic changes and how study of these mutations and their effects can reveal important and complex aspects of cell biology that may otherwise be beyond current appreciation. I make use of model systems.

My main research interest is the molecular genetics and biology of the neuronal ceroid lipofuscinoses (NCL) or Batten disease, a group of inherited neurodegenerative diseases that affect lysosome homeostasis. This group of diseases are rare but understanding their biology may open new avenues for understanding more common neurodegenerative conditions as well as the basic biology of neurons and associated cells. When I began this work none of the genes had been identified so my initial research strategy was one of genetic linkage, eventually progressing to the molecular and cell biology of the genes I identified. Fourteen genes have now been identified. I work closely with others whose aim is to identify the remaining NCL disease genes by pooling resources and expertise. I curate the NCL Resource web site, which acts as a gateway for Batten disease and includes the Mutation Database which I maintain on behalf of the international NCL community (http://www.ucl.ac.uk/ncl).

Within my own laboratory I have a particular interest in the biology of CLN3, a highly conserved gene, and of CLN6 and CLN8, vertebrate genes, whose functions remain elusive. We currently use mammalian systems and the model organism Schizosaccharomyces pombe and have studied their location, topology, trafficking signals, interacting partners and effect on cells of complete loss of function. The function of CLN3 is complex and more important than was expected, and the fission yeast model system has recently revealed novel aspects of its function including a role in polarisation of lipid domains and F-actin, and trafficking, as well as effects on vacuole homeostasis, that can be explained by a role upstream of the lysosome. These effects also translate into mammalian defects, revealed by RNAi. Significantly we discovered that an intragenic deletion of CLN3 shared by most patients with juvenile NCL does not completely abolish CLN3 function, which has important implications for future therapy development. We are using various screening strategies to identify genes and small molecules that restore defects associated with loss of CLN3 function. We are currently exploring the challenges of developing a therapy that targets the visual loss in NCL since this would significantly improve the quality of life of affected children, with the ultimate target being the brain.

Recently the potential of fission yeast as a model system for mammalian cell biology that is surprisingly under exploited has allowed me to develop a system to study membrane retrieval from the vacuole, a process that has escaped previous attempts to completely decipher and which may be similar to other intracellular membrane budding events. This approach has already shown the requirement for several genes that also underlie disease and promises to reveal numerous further genes involved in this process.